by Psychedelic drugs have shown promise as treatments for difficult-to-treat depression. Now, scientists have a possible explanation for why: The drugs may be able to slip through the outer membranes of brain cells and essentially flip switches inside the cells that other depression treatments can’t.
The findings of the new study were published on February 16 in the journal Science (opens in new tab)may explain why, in some cases, psychedelics, combined with talk therapy, work better and faster for patients than traditional antidepressants, The Scientist reported (opens in new tab).
Psychedelics include LSD. N,N-Dimethyltryptamine (DMT), found in the psychoactive drink ayahuasca. and psilocybin, the active compound in magic mushrooms. All of these substances are known to bind to a structure called the serotonin 2A receptor, which binds to the chemical messenger serotonin. These receptors occur in high concentrations within the wrinkled surface of the brain, the cerebral cortex, and can be found both on the outer surface of brain cells and inside the cells.
In particular, in cells of the cerebral cortex, the receptors can be found on the surface of the cells and clustered around the so-called Golgi body inside the cell, which is responsible for the packaging and transport of proteins, the researchers said.
Related: LSD alters consciousness by breaking down barriers in the brain
Previous research suggests that the beneficial effects of psychedelics may come from their ability to activate serotonin 2A receptors, which, in turn, encourages brain cells to create new connections with one another. But since serotonin can also activate these receptors, there was a question of why psychedelics seem to work differently than traditional antidepressants, senior author David Olsondirector of the Institute for Psychedelics and Neurotherapeutics at the University of California, Davis, told The Scientist.
(Antidepressants—including selective serotonin reuptake inhibitors, or SSRIs—usually work by increasing the amount of serotonin in the spaces between brain cells.)
Through several experiments in laboratory dishes and rodents, Olson’s team found that although serotonin readily binds to receptors on the outside of brain cells, it cannot easily pass through the cells’ fatty outer membranes to reach additional receptors inside. . Similar to how water and oil don’t mix, serotonin can’t easily pass through cell membranes because their chemical structures don’t separate.
However, the team found that many psychedelic drugs can slip right through these membranes. This is because they are much less polar than serotonin, meaning they are fatter and do not have a positive and negative end. Once inside a brain cell, psychedelics bind to internal serotonin 2A receptors that serotonin cannot reach.
In their experiments, the team found that by modifying serotonin to make it less polar, they could enhance the molecules’ ability to make new connections between neurons. This likely happened because the chemical crossed the cell membranes and activated their internal serotonin receptors, the team hypothesized.
They also showed the opposite effect. When the researchers modified DMT and psilocin (which the body produces when it breaks down psilocybin) to make them more polar, they found that these modified drugs were less able to cross the membranes of rat neurons and therefore could not enhance the their connectivity.
The team also genetically modified mice so that serotonin could pass into their neurons more easily and found that the chemical enhanced brain connectivity like a psychedelic would, according to The Scientist.
The study cannot completely rule out that serotonin could cross cell membranes to some extent, The Scientist reported. However, research hints that psychedelics may treat depression, in part, by triggering effects in the brain that standard antidepressants typically cannot.
The study also raises questions about why brain cells contain so many receptors that serotonin can’t reach – it could be that a different chemical can access the receptors and activate them, or perhaps the receptors build up in the cell only temporarily as they wait for it to be sent to the cell surface, Olson suggested.
Read more at The scientist (opens in new tab).
